Digestive histopathological presentation of IPEX syndrome

Abstract

Immunodysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX) syndrome is a well recognized and particularly severe form of autoimmune enteropathy. It has an X-linked recessive transmission, and is caused by mutations in the FOXP3 gene. We studied the intestinal morphological changes characterizing IPEX syndrome in a series of 12 children with a molecularly confirmed diagnosis. Histological examination of duodenal, gastric and colonic biopsies were retrospectively reviewed and compared by two independent experienced pathologists. In parallel, the presence of circulating anti-enterocyte antibodies was analysed using an indirect immunofluorescence technique and a quantitative radioligand assay against the 75-kDa autoantigen. The morphology of the inflammatory gut lesions could be categorized into three different entities, namely graft-vs-host disease-like changes (9/12 patients), a coeliac disease-like pattern (2/12) and an enteropathy with a complete depletion of goblet cells (1/12). Our results do not suggest any phenotypegenotype correlation. Circulating antibodies were detected in all 12 patients, with an anti-brush border pattern (11/12) and anti-goblet cell antibodies (1/12), as well as by a radioligand assay. The histological presentation of autoimmune enteropathy is rather variable. However, a graft-vs-host disease-like pattern associated with positive anti-enterocyte antibodies is the most frequent intestinal presentation of IPEX syndrome, and constitutes a very valuable tool for pathologists to suspect this diagnosis.

Colitis mimicking graft-versus-host disease during treatment with the anti-CCR4 monoclonal antibody, mogamulizumab

“…These findings strongly support the possibility that the activation of the auto-reactive immune system mainly induced by cytotoxic T-cells following the depletion of effector Treg by mogamulizumab may have led to the development of colitis mimicking acute GVHD. More importantly, intestinal GVHD-like changes accompanied with watery diarrhea have been known in patients with immunodysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX) syndrome characterized by Treg defect caused by mutations in the FOXP3 gene [18]. It might be raised a concern that addition of cytotoxic agents to mogamulizumab enhanced the risk; however, it is more likely that profound depletion of Treg after multiple cycles of mogamulizumab was related to this irAEs.…”

Gastrointestinal immunity against tryptophan hydroxylase-1, aromatic L-amino-acid decarboxylase, AIE-75, villin and Paneth cells in APECED

“…Autoantibodies against the two epithelial enterocytic antigens AIE-75 and villin, targeted in autoimmune enteropathy [23] and IPEX [24][25][26], were found in 33% and 29% of our patients with lower GI symptoms, respectively. Villin expression was found to be reduced and aberrantly located in 13 intestinal APECED samples (9 duodenum, 2 ileum, 1 colon and rectum; 9 patients) compared to reference samples.…”

Pediatric autoimmune enteropathy: an entity frequently associated with immunodeficiency disorders

“…32 Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy results from mutations in the AIRE gene, which modulates transcription of peripheral self-antigens in the thymus, presented by HLA molecules to maturing T cells. 33 ITCH deficiency was recently described within a large Old Order Amish kindred consisting of children presenting with organomegaly, failure to thrive, developmental delay, dysmorphic features and multisystem autoimmune diseases.…”